description Serotonin plays critical roles as a neurotransmitter, neuromodulator and hormone. Therapeutics for many psychiatric disorders, including major depression, anxiety disorders and eating disorders, target serotonin signaling pathways in the brain. Understanding molecular mechanisms that regulate serotonin signaling is therefore essential both for understanding the causes of many types of neurological and psychiatric illness and for developing new therapeutics. The roundworm C. elegans is a powerful model for genetic and molecular studies of nervous system function. A synapse between serotonergic motor neurons and muscles of the reproductive system drives the reproductive behavior of the C. elegans hermaphrodite, egg laying. Through genetic studies of egg-laying behavior, we have discovered that neuropeptides modulate serotonin signaling in the C. elegans reproductive system by directly inhibiting serotonergic motor neurons. Some of these modulatory neuropeptides are provided by a pair of sensory neurons, the BAG neurons, which are stimulated by environmental carbon dioxide. The aim of this proposal is to determine physiological and molecular mechanisms required for the activation of peptidergic sensory neurons by carbon dioxide, and mechanisms by which neuropeptides inhibit the serotonergic neurons that they target. PUBLIC HEALTH RELEVANCE: Serotonin and neuropeptides are important neurochemicals that are implicated in the etiologies of many psychiatric and neurological disorders, including major depression, eating disorders, sleep disorders, aggression, and addiction. There is an urgent need to identify mechanisms that function in these neurochemical signaling pathways in order to better understand the causes of brain disorders and to design safer and more effective therapeutics for their treatment. The aim of this proposal is to use behavioral genetics and in vivo functional imaging of a C. elegans model to determine novel molecular mechanisms that act in a neuropeptide signaling pathway that regulates serotonin release. Importantly, in our model, the neurons that provide modulatory neuropeptides are chemosensory neurons that are activated by carbon dioxide (CO2). Our studies will therefore address molecular mechanisms by which CO2 regulates chemosensitive neurons, which in humans are critical regulators of respiration and whose dysfunction has been associated with anxiety disorders. Because our model for the study of serotonin and neuropeptide signaling is the neuromusculature of the nematode reproductive system, any mechanisms we discover that are not conserved between nematodes and mammals would be attractive targets for therapeutics to treat parasitic nematode infections.